AVID200, first-in-class TGF-beta 1 and 3 selective and potent inhibitor: Safety and biomarker results of a phase I monotherapy dose-escalation study in patients with advanced solid tumors.
Timothy A. Yap, Nehal J. Lakhani, Daniel Vilarim Araújo, Jordi Rodon Ahnert, Sreenivasa R Chandana, Manish Sharma, Jean-François Denis, Tina Gruosso, Gilles Tremblay, Maureen O’Connor, Ria Ghosh, Sandra Sinclair, Debra L. Wood, Paul I. Nadler, Lillian L. Siu
Abstract
3587 Background: AVID200 is a rationally designed first-in-class, selective inhibitor of transforming growth factor-beta (TGF-beta) that neutralizes TGF-beta 1 & 3 with pM potency and 4,000 fold selectivity over TGF-beta 2. TGF-beta 1 & 3 signaling has been associated with immune checkpoint inhibitor resistance and immunosuppression in the tumor microenvironment while TGF-beta 2 is required for normal cardiac function and hematopoiesis. Methods: NCT03834662 (AVID200-03) is a multicenter Phase 1 study following a standard 3 + 3 dose escalation to evaluate safety and tolerability of AVID200 given IV every 3 weeks to patients (pts) with advanced solid tumors. Peripheral target engagement was assessed in blood by ELISA and a cell-based functional assay, and in skin biopsies by immunohistochemistry (IHC). Pharmacodynamic markers of TGF-beta signal modulation and immune activation were evaluated in serum using the InflammationMAP v 1.0 (Myriad RBM) and in paired tumor biopsies by IHC and Imaging Mass Cytometry. Results: Nineteen pts (ECOG 0-1, median age 63 [range 39-77], 52.6% male) received AVID200 at 3 planned dose levels of 180 (N = 7), 550 (N = 6), and 1100 mg/m 2 (N = 6) (~5, 15, and 30 mg/kg). The maximum tolerated dose was not reached. Three Grade (G) 3 treatment-related adverse events (TRAEs) were reported in 2 pts (diarrhea and lipase elevation, anemia); no > G3 TRAEs were observed. Serum exposure was dose-proportional and AVID200 sequestered all active TGF-beta 1 & 3, but not beta 2, in blood across the entire dosing period at all dose levels, providing proof-of-mechanism of AVID200. SMAD2 phosphorylation in skin biopsies was detectably reduced on Day 4 at 15 and 30 mg/kg. Pro-inflammatory markers in serum were increased on Day 8 versus baseline in a dose-dependent manner. Tumor biopsies of pts treated at 15 mg/kg showed modulation of TGF-beta signaling and immune activation. A best response of RECIST stable disease > 12 weeks was observed in 2 pts: 1 with adenoid cystic carcinoma (5 mg/kg; 8.7 months); 1 with breast carcinoma (30 mg/kg; 3.1 months). Conclusions: AVID200 was safe and well tolerated at dose levels of 5-30 mg/kg, with peripheral target engagement across the entire dosing period. AVID200 led to TGF-beta target modulation and immune activation. These data provide proof-of-principle that AVID200-mediated selective and potent inhibition of TGF-beta 1 & 3 is feasible in the clinic. The AVID200 monotherapy data warrant exploration of rational combination with a PD-(L)1 inhibitor. Clinical trial information: NCT03834662 .